Certain xcex942 double bond cephalosporin derivatives are known to be valuable intermediates for the manufacture of pharmacologically useful cephalosporins as described in EP-A-620 225 and in EP-A-849 269. In a known process these cephalosporin derivatives are prepared from a phosphonium salt and a xcex942 double bond aldehyde in the presence of a base such as 1,2-butyleneoxide or triethylamine in an inert solvent to yield the xcex943-isomer of the cephalosporin derivative. This is due to the fact that the xcex942 double bond is very sensitive towards bases in solution and readily migrates to the 3-position. The formation of the xcex943-reaction product necessitates the correction of the position of the double bond to the desired 2-position by a two-step redox sequence. In the known process this is effected by oxidation to the corresponding sulfoxide with hydrogen peroxide or a peracid and deoxygenation thereof with phosphorus tribromide. These reagents, in particular the latter, are corrosive and dangerous to use on a large scale.
Efforts to obtain these cephalosporin derivatives directly via reaction of the phosphonium salt and xcex942 aldehyde are hampered by the sensitivity of xcex942 cephalosporins to bases in solution. Therefore, it would be useful to develop a process in which this isomerization does not occur.
The present invention is concerned with a process for producing compounds of formula 
wherein
R1 is an amino protecting group,
R2 is a carboxy protecting group, and
R is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl
which comprises treating a phosphonium salt of formula 
in a toluene reaction mixture with a base, said base being present in a molar amount which is less than the molar amount of said phosphonium salt, to form an ylide of formula 
coupling the ylide of formula III with an aldehyde of formula 
by adding to the reaction mixture a solution of the aldehyde of formula IV in a polar solvent at a temperature of from about xe2x88x9280xc2x0 C. to about 0xc2x0 C.; to produce the compound of formula I.
Preferably, the process involves the manufacture of cephalosporin derivatives of the formula 
wherein
R1 is an amino protecting group,
R2 is a carboxy protecting group, and
R is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and allyloxycarbonyl which is substituted on a ring nitrogen of pyrrolidinyl.
The process is characterized in that it comprises converting a phosphonium salt of the formula 
wherein R is as above and Ph represents phenyl,
in toluene by treatment with a base into the corresponding ylide of the formula 
wherein R and Ph are as above,
and reacting same with a solution in a polar solvent of an aldehyde of the formula 
wherein R1 and R2 are as above,
at a temperature of from about xe2x88x9280xc2x0 C. to about 0xc2x0 C., the phosphonium salt II, base and aldehyde IV being employed in a molar ratio of about 1.15:1.1:1.0 to 1.3:1.25:1.0. The molar amount of base is less than that of the phosphonium salt.
Accordingly, this invention is directed to a method of producing a compound of formula 
wherein
R1 is an amino protecting group,
R2 is a carboxy protecting group, and
R2 is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl-lower alkyl, aryl and the heterocyclyl moieties being unsubstituted or substituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and allyloxycarbonyl which is substituted on a ring nitrogen of pyrrolidinyl
which comprises treating a phosphonium salt of formula 
in a toluene reaction mixture with a base, said base being present in a molar amount which is less than the molar amount of said phosphonium salt, to to form an ylide of formula 
coupling the ylide of formula III to the aldehyde of formula 
by adding to the reaction mixture a solution of the aldehyde of formula IV in a polar solvent at a temperature of from about xe2x88x9280xc2x0 C. to about 0xc2x0 C. (preferably about xe2x88x9280xc2x0 C. to about xe2x88x9260xc2x0 C., most preferably about xe2x88x9270xc2x0 C.); wherein said base, ylide, and aldehyde are present in the reaction mixture during the formation of the compound of formula I in molar ratio of about 1.15:1.1:1.0 to 1.3:1.25:1.0, and preferably about 1.2:1.15:1.0, to produce the compound of formula I. It is important that the molar amount of base is less than that of the phosphonium salt.
A preferred polar solvent is tetrahydrofuran. Preferred bases include aqueous sodium hydroxide and potassium tert.butoxide in tetrahydrofuran.
When the base is potassium tert.butoxide in tetrahydrofuran, it is preferable that the toluene reaction mixture further comprises methylene chloride and the polar solvent is tetrahydrofuran, in the preferred weight ratio of about 2:1:1 to 5:2:1. Under these conditions, a preferred R is N-substituted 3-pyrrolidinyl, especially N-allyloxycarbonyl-3-pyrrolidinyl.
Preferred aldehydes of formula IV are diphenylmethyl (6R,7R)-7-(1-tert-butoxyformamido)-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate and 4-methoxybenzyl (6R,7R)-7-phenylacetylamino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
It is preferred that R is selected from substituted lower alkyl (such as 2,2,2-trifluoroethyl), or unsubstituted or substituted cycloalkyl (such as cyclopropyl or cyclopropylmethyl). Heterocyclyl is also a preferred R, such as 5 or 6-membered rings containing one or two heteroatoms (preferably nitrogen), especially substituted heterocyclyl such as N-substituted 3-pyrrolidinyl (such as N-allyloxycarbonyl-3-pyrrolidinyl).
As used herein, the terms xe2x80x9clower alkylxe2x80x9d and xe2x80x9coptionally substituted lower alkylxe2x80x9d refer to both straight and branched chain saturated hydrocarbon groups having 1 to 8, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like. The lower alkyl groups can be unsubstituted or substituted by at least one substituent such as halogen. Preferred substituents are fluoro, examples of substituted lower alkyl are trifluoromethyl, 2,2,2-trifluoroethyl, perfluorohexyl and the like.
By term xe2x80x9clower alkoxyxe2x80x9d is meant an ether group wherein alkyl is as defined above. Examples are methoxy, ethoxy, propyloxy and the like.
By the term xe2x80x9ccycloalkylxe2x80x9d is meant a 3-7 membered saturated carbocyclic ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. xe2x80x9cCycloalkyl-lower alkylxe2x80x9d is an alkyl group as defined above with an attached cycloalkyl ring. Preferred cycloalkyl-lower alkyls are for example cyclopropylmethyl and cyclopropylethyl. By the term xe2x80x9ccycloalkenylxe2x80x9d is meant a 4-7 membered carbocyclic ring having at least one olefinic double bond, e.g. cyclopentenyl.
As used herein, xe2x80x9clower alkenylxe2x80x9d refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. vinyl, allyl, and the like.
As used herein, xe2x80x9clower alkynylxe2x80x9d refers to an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one triple bond, e.g. ethynyl, 1-propynyl, 2-propynyl.
The term xe2x80x9chalogenxe2x80x9d used herein refers to chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro.
By the term xe2x80x9carylxe2x80x9d is meant a radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen which can be substituted or unsubstituted. The aromatic hydrocarbon can be mononuclear or polynuclear. Examples of aryl radicals of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cumenyl and the like. Examples of aryl radicals of the polynuclear type include naphthyl, anthryl, phenanthryl and the like. The aryl group can have at least one substituent selected from halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy and trifluoromethyl. Examples include 2-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl and the like. The abbreviation xe2x80x9cPhxe2x80x9d such as used in formula II stand for phenyl.
By the term xe2x80x9caryl-lower alkylxe2x80x9d is meant a lower alkyl group containing an aryl group as defined above, for example benzyl or benzhydryl.
As used herein, xe2x80x9cheterocyclylxe2x80x9d refers to an unsaturated or saturated, unsubstituted or substituted 5-, 6-, or 7-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heterocyclic rings include, but are not limited to, e.g., the following groups: pyrrolidinyl, pyridinyl, pyridiniumyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxide-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl, azetidinyl, furyl, hexamethyleneiminyl, oxepanyl, 1H-azepinyl, thiophenyl, tetrahydro-thiophenyl, 3H-1,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadithiolyl, isoxazolyl, isothiazolyl, 4H-1,2,4-oxadiazinyl, 1,2,5-oxathiazinyl, 1,2,3,5-oxathiadiazinyl, 1,3,4-thiadiazepinyl, 1,2,5,6-oxatriazepinyl, oxazolidinyl, tetrahydrothienyl, and the like. Preferred heterocyclic rings are pyridinyl, pyridiniumyl, piperidyl, pyrrolidinyl (particularly 3-pyrrolidinyl) and azetidinyl. Substituents for the heterocyclic ring include lower-alkyl, lower alkoxy, halogen, trifluoro-methyl, trichloroethyl, amino, mercapto, hydroxy, carboxy and carbamoyl. Preferred examples of substituted heterocyclic rings include 5-methyl-isoxazol-3-yl, N-methyl-pyridinium-2-yl, N-methyl-pyrrolidinyl, 1-methyl-tetrazolyl, N-allyloxycarbonyl-3-pyrrolidinyl, and methyl-pyridinium-2-yl.
The heterocyclic ring can also be substituted by an optionally substituted phenyl ring such as 2,6-dichlorophenyl. Preferred is 2,6-dichlorophenyl-5-methyl-isoxazolyl. A further substituent of the heterocyclic ring is oxo, such as in 2-oxo-oxazolidin-3-yl and 1,1-dioxo-tetrahydrothien-3-yl. The heterocyclic ring can also be fused together with a benzene ring.
As used herein, xe2x80x9cheterocyclyl-lower alkylxe2x80x9d refers to a lower alkyl group containing a heterocyclic group as defined above, e.g. tetrazolyl-methyl, tetrahydrofuranyl-methyl, thiophenyl-methyl or benzimidazolyl-methyl.
Amino protecting groups are groups which can be cleaved off under known conditions to yield the free amino group. Possible amino-protecting groups R1 are those employed in peptide chemistry, such as an alkoxycarbonyl group, e.g., t-butoxycarbonyl, etc., a substituted alkoxycarbonyl group, e.g., trichloroethoxycarbonyl etc., an arylalkanoyl group, e.g. phenylacetyl, a heteroarylalkanoyl group, e.g. 2-thienyl-acetyl or 2-furyl-acetyl; an optionally substituted aralkyloxycarbonyl group, e.g., p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, an aralkyl group such as trityl or benzhydryl or a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl. Preferred amino-protecting groups are t-butoxycarbonyl (t-BOC), phenylacetyl and trityl.
Carboxy protecting groups are groups which can be cleaved off under known conditions to yield the carboxy group. As carboxy protecting groups R2 one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, the ester protecting group being exemplified by, for example, t-butyl, p-nitrobenzyl, p-methoxybenzyl, allyl or benzhydryl.
Efforts to obtain compounds I directly via reaction of compounds II and IV are hampered by the sensitivity of xcex942 cephalosporins, such as compounds I and IV, to bases in solution. However, it has been found that the xcex942-aldehyde IV as well as the reaction product I dissolved in toluene are stable and do not isomerize in the presence of the ylide III formed from the phosphonium salt II as long as the molar ratio of the base is not in excess of that of the starting phosphonium salt II. Apparently the basicity of the ylide III, which is present in slight excess, is too weak to induce the isomerization of compounds IV and I in toluene.
In carrying out the process in accordance to the invention, the phosphonium salt is preferably dispersed in toluene, or a mixture of toluene and methylene chloride, and submitted to treatment with a base, e.g. with aqueous alkali, e.g. 0.1N-1N aqueous NaOH or KOH or, in the absence of water, with sodium or potassium tert.-butylate in a polar organic solvent such as tetrahydrofuran or dioxane, preferably in tetrahydrofuran. In adding the alkali tert.-butylate in tetrahydrofuran the deprotonation step in forming the ylide III is accelerated and the advantage is reached, that addition of a solid to the system is avoided, which is of advantage due to the low reaction temperature. Also, the system can in this way advantageously be precooled to reaction temperature prior to adding the alkali tert.butylate in tetrahydrofuran.
The resulting ylide III solution/suspension, if not already cooled to reaction temperature as above, is now brought thereto, i.e. to between about 0xc2x0 C. and about xe2x88x9280xc2x0 C., preferably to about xe2x88x9260xc2x0 C. to about xe2x88x9280xc2x0 C., most preferably to about xe2x88x9270xc2x0 C., and brought to reaction with the aldehyde IV in solution in a polar organic solvent such as tetrahydrofuran or dioxane, preferably tetrahydrofuran. The molar ratio of the reactants (phosphonium salt II:alkali:aldehyde IV as given above) avoids the undesired xcex942/xcex943 migration of the double bond of the resulting end product I, particularly when the molar ratio is about 1.2:1.15:1.0.
The reaction time varies between about xc2xd hour and 2 hours.
In preferred embodiments of the process of the invention diphenylmethyl (6R,7R)-7-(1-tert-butoxyformamido)-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate or 4-methoxybenzyl (6R,7R)-7-phenylacetylamino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate is used as starting aldehyde of formula IV.
Preferred starting phosphonium salts of formula II are such wherein R is 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or N-substituted 3-pyrrolidinyl, such as N-allyloxycarbonyl-3-pyrrolidinyl. The allyloxycarbonyl group is a protecting group which is subsequently split off to yield end products of formula V below, in which R is 3-pyrrolidinyl.
Where R is N-substituted 3-pyrrolidinyl, such as N-allyloxycarbonyl-3-pyrrolidinyl, the process is preferably carried out in non-aqueous phase in a mixture of toluene, methylene chloride and tetrahydrofuran, preferably in a weight ratio of between about 2:1:1 and 5:2:1. In a preferred embodiment the phosphonium salt II is dissolved in methylene chloride, toluene is added, followed by potassium tert.-butylate in tetrahydrofuran solution and finally by aldehyde IV in tetrahydrofuran and reacted for xc2xd-2 hours at about xe2x88x9280xc2x0 C. to xe2x88x9260xc2x0 C.
The resulting toluene reaction mixture contains crude reaction product of formula I. In order to avoid migration of the xcex942 double bond to the 3-position, work-up is effected in aqueous acid, e.g. by adding 0.1-1N aqueous HCl or citric acid. By extraction of the so acidified reaction mixture in usual manner, recovery of the toluene solution and evaporation thereof a crude product of formula I is obtained, which can be used for further reactions to pharmacologically useful cephalosporins. If desired, the crude product can be further purified in known manner e.g. by flash chromatography on silica gel with a suitable solvent or solvent mixture, e.g. methylene chloride, toluene:ethyl acetate or n-hexane:ethyl acetate.
The process of the present invention offers easier access to pharmacologically useful cephalosporins e.g. of the formula 
wherein
R is as above,
X is xe2x80x94CHxe2x80x94 or nitrogen, and
R3 is hydrogen, optionally substituted lower alkyl, cycloalkyl, benzyl, trityl, acetyl or tetrahydropyranyl, and their pharmaceutically acceptable salts and in vivo cleavable esters.
The process for arriving at compounds V is thus shortened, offers higher yields and avoids problematic reagents. Compounds V can be obtained from compounds I according to directions given in EP-A 620 225 and in EP-A-849 269.
In a preferred embodiment of compounds V R is 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or 3-pyrrolidinyl, X is xe2x80x94CHxe2x80x94 and N and R3 is hydrogen.